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Bringing Clarity to the Murky Problem of Cardiac Allograft Vasculopathy

  • Ronald G. Gill
    Correspondence
    Address correspondence to Ronald G. Gill, Ph.D., Department of Surgery, University of Colorado Denver, 1775 Aurora Ct., Aurora, CO 80045.
    Affiliations
    Department of Surgery, University of Colorado Denver, Aurora, Colorado
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      Although most published studies involving preclinical mouse models of cardiac allograft rejection tend to center on the issues of acute rejection and tolerance induction, arguably the more pressing need in the field of clinical transplantation is better understanding of chronic allograft injury. That is, chronic graft injury is a far greater current clinical problem than is early graft loss due to acute rejection. In heart transplantation, cardiac allograft vasculopathy (CAV) is a form of pronounced coronary artery disease that occurs over time after transplant
      • Ramzy D.
      • Rao V.
      • Brahm J.
      • Miriuka S.
      • Delgado D.
      • Ross H.J.
      Cardiac allograft vasculopathy: a review.
      and remains the major source of transplant loss and recipient mortality.
      • Kirk R.
      • Edwards L.B.
      • Kucheryavaya A.Y.
      • Aurora P.
      • Christie J.D.
      • Dobbels F.
      • Rahmel A.O.
      • Stehlik J.
      • Hertz M.I.
      The Registry of the International Society for Heart and Lung Transplantation: thirteenth official pediatric heart transplantation report--2010.
      ,
      • Lu W.H.
      • Palatnik K.
      • Fishbein G.A.
      • Lai C.
      • Levi D.S.
      • Perens G.
      • Alejos J.
      • Kobashigawa J.
      • Fishbein M.C.
      Diverse morphologic manifestations of cardiac allograft vasculopathy: a pathologic study of 64 allograft hearts.
      Moreover, it has become increasingly apparent over the past several years that the development of donor-specific antibodies (DSAs) is strongly associated with CAV and chronic allograft rejection in general through the process of antibody-mediated rejection (AMR).
      • Loupy A.
      • Lefaucheur C.
      Antibody-mediated rejection of solid-organ allografts.
      ,
      • Berry G.J.
      • Burke M.M.
      • Andersen C.
      • Bruneval P.
      • Fedrigo M.
      • Fishbein M.C.
      • Goddard M.
      • Hammond E.H.
      • Leone O.
      • Marboe C.
      • Miller D.
      • Neil D.
      • Rassl D.
      • Revelo M.P.
      • Rice A.
      • Rene Rodriguez E.
      • Stewart S.
      • Tan C.D.
      • Winters G.L.
      • West L.
      • Mehra M.R.
      • Angelini A.
      The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation.
      More importantly, once DSA is generated and CAV occurs, limited treatment options are available for preventing eventual allograft failure. As such, in addition to advancing the study of clinical acute and chronic allograft rejection, it is imperative to develop preclinical animal models that permit greater mechanistic insights into the pathogenesis of CAV. Identifying suitable mouse models of CAV, especially involving AMR, has been challenging because useful mouse models need to avoid primary acute rejection and yet be permissive for generating longer-term chronic allograft injury. Early mouse models used to generate CAV employed limited antigen disparity between donor and recipient, such as responses to the minor male H-Y antigen in female recipients
      • Kaul A.M.
      • Goparaju S.
      • Dvorina N.
      • Iida S.
      • Keslar K.S.
      • de la Motte C.A.
      • Valujskikh A.
      • Fairchild R.L.
      • Baldwin 3rd, W.M.
      Acute and chronic rejection: compartmentalization and kinetics of counterbalancing signals in cardiac transplants.
      or to donors that differ from the host at a single major histocompatibility complex class II molecule.
      • Ardehali A.
      • Fischbein M.P.
      • Yun J.
      • Irie Y.
      • Fishbein M.C.
      • Laks H.
      Indirect alloreactivity and chronic rejection.
      • Sayegh M.H.
      • Wu Z.
      • Hancock W.W.
      • Langmuir P.B.
      • Mata M.
      • Sandner S.
      • Kishimoto K.
      • Sho M.
      • Palmer E.
      • Mitchell R.N.
      • Turka L.A.
      Allograft rejection in a new allospecific CD4+ TCR transgenic mouse.
      • Zhao Y.
      • Chen S.
      • Lan P.
      • Wu C.
      • Dou Y.
      • Xiao X.
      • Zhang Z.
      • Minze L.
      • He X.
      • Chen W.
      • Li X.C.
      Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model.
      However, these models tended to largely invoke a cellular form of chronic rejection rather than clearly reflect DSA-associated CAV. Another means of developing CAV in mice is through the treatment of recipients with transient or suboptimal immune-modifying agents, which results in chronic rather than acute rejection, although the role of DSA in these models is less defined.
      • Zhao Y.
      • Chen S.
      • Lan P.
      • Wu C.
      • Dou Y.
      • Xiao X.
      • Zhang Z.
      • Minze L.
      • He X.
      • Chen W.
      • Li X.C.
      Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model.
      • Orosz C.G.
      • Wakely E.
      • Bergese S.D.
      • VanBuskirk A.M.
      • Ferguson R.M.
      • Mullet D.
      • Apseloff G.
      • Gerber N.
      Prevention of murine cardiac allograft rejection and gallium nitrate: comparison with anti-CD4 monoclonal antibody.
      • Tsuda H.
      • Dvorina N.
      • Keslar K.S.
      • Nevarez-Mejia J.
      • Valenzuela N.M.
      • Reed E.F.
      • Fairchild R.L.
      • Baldwin 3rd, W.M.
      Molecular signature of antibody-mediated chronic vasculopathy in heart allografts in a novel mouse model.
      A more recent approach to assess the role of DSA in triggering CAV is through the direct transfer of antibodies specific for donor major histocompatibility complex class I to immune-deficient recipients bearing a cardiac allograft.
      • Hirohashi T.
      • Uehara S.
      • Chase C.M.
      • DellaPelle P.
      • Madsen J.C.
      • Russell P.S.
      • Colvin R.B.
      Complement independent antibody-mediated endarteritis and transplant arteriopathy in mice.
      ,
      • Lin C.M.
      • Plenter R.J.
      • Coulombe M.
      • Gill R.G.
      Interferon gamma and contact-dependent cytotoxicity are each rate limiting for natural killer cell-mediated antibody-dependent chronic rejection.
      While these varied approaches have proven useful for studying some aspects of CAV in mice, there remains an onging need to develop improved animal models of DSA-associated CAV.
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      Linked Article

      • Molecular Signature of Antibody-Mediated Chronic Vasculopathy in Heart Allografts in a Novel Mouse Model
        The American Journal of PathologyVol. 192Issue 7
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          Cardiac allograft vasculopathy (CAV) limits the long-term success of heart transplants. Generation of donor-specific antibodies (DSAs) is associated with increased incidence of CAV clinically, but mechanisms underlying development of this pathology remain poorly understood. Major histocompatibility complex–mismatched A/J cardiac allografts in B6.CCR5−/− recipients have been reported to undergo acute rejection with little T-cell infiltration, but intense deposition of C4d in large vessels and capillaries of the graft accompanied by high titers of DSA.
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